Melatonin attenuates post-resuscitation myocardial dysfunction with associated improvements in mitochondrial dynamics in rats

Cardiac arrest (CA) remains a leading cause of death worldwide despite advances in cardiopulmonary resuscitation (CPR) and post-resuscitation care. Post-resuscitation myocardial dysfunction (PRMD) is a major determinant of early outcomes following return of spontaneous circulation (ROSC), with mitochondrial dysfunction serving as a core pathological driver; however, no specific pharmacological interventions targeting mitochondrial protection are currently available. Although melatonin (Mel) has demonstrated cardioprotective effects in ischemia–reperfusion injury, its role in PRMD is not fully understood. In this study, a rat model of CA/CPR was induced by ventricular fibrillation, and Mel (10 mg/kg) was administered intravenously 30 min post-ROSC. An in vitro hypoxia/reoxygenation model using H9c2 cells was employed for mechanistic validation. Mel improved post-resuscitation hemodynamics and left ventricular function, reduced arrhythmia burden and myocardial injury, and attenuated inflammation, oxidative stress, and apoptosis. It also preserved mitochondrial ultrastructure, stabilized mitochondrial membrane potential, inhibited opening of the mitochondrial permeability transition pore, and restored ATP production and the NAD + /NADH ratio. Mechanistically, Mel downregulated mitochondrial fission-related proteins, including phosphorylated DRP1, Fis1, and MFF, while upregulating fusion-related proteins (MFN1, MFN2, and OPA1). These findings indicate that melatonin treatment is associated with preserved mitochondrial homeostasis and improved mitochondrial fission–fusion balance in a rat model of PRMD, supporting further investigation of mitochondrial dynamics as a potential contributor to melatonin-related cardioprotection.